Genotype-Phenotype Discrepancies in Family Members With a Novel Glucokinase Mutation: Insights Into GCK-MODY and Its Interplay With Insulin Resistance

This study was undertaken to investigate the diabetogenic potential of a novel GCK variant, c.77A>T, p.Q26L, found in two family members with marked differences in diabetic phenotypes. We aimed to understand the role of GCK-Q26L in glucose metabolism and to explore whether genetic backgrounds, including polygenic risk score for insulin resistance and type 2 diabetes, contribute to diabetes manifestations. We found that GCK-Q26L is a pathogenic mutation leading to GCK-MODY, with severity modulated by polygenic risk score for insulin resistance and type 2 diabetes. These findings not only expand the list of GCK-MODY causing mutations but also highlight the importance of polygenic backgrounds in the clinical presentation and management of monogenic diabetes.